tbuckley/cabot-search huggingface dataset:
Real-world, population-based study of treatments, survival and healthcare use in advanced urothelial carcinoma of the bladder.
Authors: Winson Y. Cheung, Atul Batra, Iqra A. Syed, Daniel Moldaver, Derek L. Clouthier
Journal: Journal of Clinical Oncology (2022)

e16538 Background: Prior single institutional studies and case series suggest that management of urothelial carcinoma of the bladder (UCB) can be highly variable across different centers. To better contextualize emerging therapies and their place in management, we aimed to characterize current population-based treatment patterns, outcomes, and healthcare resource utilization. Methods: Using real-world registries and administrative data, we analyzed a contemporary cohort of patients diagnosed with advanced UCB from 2010 to 2017 in the large province of Alberta, Canada. The study time period was selected to allow for adequate follow-up. The Kaplan-Meier method was used to plot estimates of overall survival (OS) and Cox proportional hazards model was constructed to determine the associations of clinical characteristics with outcomes. Summary statistics were used to describe healthcare resource use. Results: We included 1,146 advanced UCB patients. Median age was 73 (IQR 65-81) years, majority (78%) were men, and most (69%) had a Charlson comorbidity index of 0 to 1. Only 363 (32%) were referred, consulted with oncologists, and received palliative systemic therapy. Common regimens consisted of platinum-based doublet in the first-line (1L) setting and single-agent chemotherapy or immunotherapy in the second-line (2L) setting. Only 116 (32%) of the 1L treated patients proceeded to 2L. Median OS was 9.8 months (10.2 and 5.3 months in treated and untreated patients, respectively). After adjusting for confounders, receipt of at least one line of systemic therapy was associated with improved OS (HR 0.79, 95% CI 0.65-0.95, P = 0.011) as was urban residence with more access to oncology care (HR 0.82, 95% CI 0.73-0.92, P = 0.001). Median number of emergency department visits was 4 (IQR 2-7) per patient. Median number of hospitalizations and duration of admissions were 3 (IQR 2-5) per patient and 10 (IQR 6-16) days, respectively. Conclusions: In our population-based sample, the poor prognosis of UCB may be largely attributed to the low receipt of systemic therapy rather than the burden of comorbidities or acute care encounters. Since treatment attrition is significant, efforts to streamline referral to and consultation with oncologists at the time of metastatic diagnosis may optimize the use of appropriate systemic therapies and improve survival. This is increasingly important as novel, more effective therapies for advanced UCB are introduced into the treatment armamentarium.
Health outcomes modelling of RNA-based versus DNA-based detection of driver gene rearrangements in non-small cell lung cancer.
Authors: Tomi Jun, William K. Oh, Eric Schadt, Mitchell Higashi
Journal: Journal of Clinical Oncology (2022)

e18837 Background: There are several FDA-approved targeted therapies for NSCLC with driver gene rearrangements (DGRs) involving ALK, ROS1, RET, NTRK1-3, and MET exon 14. DNA-based sequencing panels miss 15-20% of DGRs compared to RNA-based methods (Benayed et al., 2019; Solomon et al., 2020). We modelled the years of life gained by using RNA- instead of DNA-based methods for DGR detection. Methods: We used the IVI-NSCLC open-source model to analyze the relationship between stable disease, progression, and death as previously described in a multi-state model. Previously reported PFS hazard ratios for targeted therapies (versus chemotherapy) treating DGRs range from 0.17 to 0.52 (Hoang et al., 2020). Therefore, we assumed that the HRs corresponding to the parameter estimates for the targeted therapy option built into the model would approximate treatment-specific relative effects of targeted therapies for DGRs (PFS = 0.3; OS = 0.8). We simulated life-years and quality-adjusted life years (QALYs) for a cohort of 1,000 patients with DGRs matched to appropriate targeted therapies over a 5-year time horizon. We used population-level prevalence data to estimate the number of patients with metastatic NSCLC and DGRs. We then estimated the number of false negatives generated by DNA-only sequencing and calculated the additional life-years gained if RNA-based methods were used instead. Results: In a simulated cohort of 1,000 patients with DGRs detected through RNA sequencing and receiving targeted therapy, median PFS and OS were 1.8 and 3.7 years, respectively. The use of targeted therapy (instead of chemotherapy) in these patients increased life-years by 3.46 years (95% CI, 3.04-3.90) and QALYs by 2.27 years (95% CI 1.91-2.71) on average per patient. There were approximately 235,768 new lung cancers in the US in 2021, 56% of which were metastatic at diagnosis (SEER). Approximately 50% of lung cancers are adenocarcinomas, and approximately 12% of adenocarcinomas have DGRs: ALK (5%) , MET (4%) , ROS1 (2%) , RET (1%) , and NTRK1-3 (&lt; 1%). Thus, there were approximately 7,922 new metastatic NSCLC cases with DGRs in 2021. Prior studies have shown that DNA-only methods have a sensitivity of 80-85% for DGRs compared to RNA-based methods. At the level of the US population, this implies 1,188-1,584 false negative cases in 2021. The clinical impact of eliminating these false negatives by using RNA- instead of DNA-based methods to identify DGRs amounts to 4,110–5,480 life-years or 2,696–3,595 QALYs gained by appropriately matching patients with DGRs to targeted therapy over chemotherapy. Conclusions: DNA-only sequencing methods have limited sensitivity for DGRs in lung cancer, leading to false negatives and missed opportunities for targeted therapy. This modeling study suggests that the elimination of such false negatives using RNA-based detection methods would lead to meaningful gains in patient outcomes.
Real-world clinical outcomes in patients with local/regional HER2-low breast cancer: An NCDB analysis.
Authors: Changchuan Jiang, Stuthi Perimbeti, Lei Deng, Qian Wang, Shipra Gandhi, Charles L. Shapiro
Journal: Journal of Clinical Oncology (2022)

558 Background: The development of novel anti-HER2 drugs opens new treatment options, including women with lower expression of HER2. This study aimed to compare local/regional HER2-low and HER2-0 breast cancer outcomes in the real world. Methods: Women diagnosed between 2010 and 2017 with clinical stage I-III breast cancers with low HER2 expression or HER2-zero (0) expression were identified in the National Cancer Database (NCDB), a nationwide oncology outcomes database in the United States. HER2-Low was defined as IHC1+ or 2+/ISH negative, whereas HER2-zero was IHC-0. The primary outcome was overall survival (OS). We performed a multivariable Cox regression model to estimate hazard ratios and adjusted for the following factors: age, race/ethnicity, education, insurance, comorbidities, grade, stage, lymph nodes, type of surgery, the type of cancer center, and if any chemotherapy, any hormonal therapy, and any adjuvant radiation in the first treatment course. Stratification factors were hormone receptor status. Subgroup analyses for those who received neoadjuvant (NAC), adjuvant (AC), and no chemotherapy were performed, and the pathologic complete response (pCR) rates in NAC groups were estimated. Results: 376,199 (68%) women with HER2-low tumors and 177,298 (32%) with HER2-0 tumors were analyzed. 336,147 (89%) of the HER2-low tumors and 141,528 (79%) of the HER2-0 tumors were HR-positive. Low HER2 expression was associated with longer OS in both HR-positive (adjusted Hazard Ratio (aHR): 0.94, 95%CI 0.93-0.96, p&lt;0.001) and HR-negative diseases (aHR: 0.88, 95%CI 0.85-0.91, p&lt;0.001). HR-positive, HER2-low tumors had statistically significantly better survival than HR-positive, HER2-0 tumors in NAC (aHR 0.84, 95%CI 0.79-0.90, p&lt;0.001) and AC (aHR 0.90, 95%CI 0.85-0.94, p&lt;0.001) groups, but not in the no-chemo group (aHR 1.02, 95%CI 1.00-1.05, p=0.09, p interaction&lt;0.001). In contrast, HR negative, HER2-low tumors had better OS than HR negative, HER2-0 tumors in all subgroups, regardless of receipt or timing of chemotherapy (NAC aHR 0.88, 95%CI 0.83-0.94, p&lt;0.001, AC aHR 0.86, 95%CI 0.81-0.92, p&lt;0.001, No chemo aHR 0.93, 95%CI 0.87-0.99, p=0.03, p interaction=0.06). In NAC groups, HER2-low expression was linked to lower pCR rates in both HR-positive (8.9% vs. 11.2%, p&lt;0.001) and HR-negative (31.2% vs. 34.1%, p&lt;0.001). Conclusions: Local/regional HER2-low breast cancer has better survival than HER2-0 breast cancer, irrespective of its hormone receptor status. The survival advantage was observed in HR-negative disease and only with receipt of chemotherapy in HR-positive breast cancer. Specific therapies, such as trastuzumab deruxtecan, have activity in HER2-low breast cancers, and other therapeutics for HER-2 low diseases should be sought.
Outcomes Following Taxation of Sugar-Sweetened Beverages
Authors: Tatiana Andreyeva, Keith Marple, Samantha Marinello, Timothy E. Moore, Lisa M. Powell
Journal: JAMA Network Open (2022)

<h3>Importance</h3> More than 45 countries and several local jurisdictions have implemented sugar-sweetened beverage (SSB) taxes to improve nutrition and population health, and evidence on their outcomes to date is essential to inform policy discussions. Responding to this need, the World Health Organization commissioned a systematic literature review on the outcomes of fiscal policies, including SSB taxes. <h3>Objective</h3> To assess the associations of implemented SSB taxes with prices, sales, consumption, diet, body weight, product changes, unintended consequences, health, and pregnancy outcomes. <h3>Data Sources</h3> Searches of 8 bibliographic databases (Business Source Complete, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, EconLit, PsycINFO, PubMed, and Scopus) were performed from database inception through June 1, 2020, with no language or setting restrictions. Grey literature was assessed using 14 sources and government websites. <h3>Study Selection</h3> The review included primary studies of implemented SSB taxes. <h3>Data Extraction and Synthesis</h3> The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. For prices, sales and consumption, results were meta-analyzed using a 3-level random-effects model. Study quality was assessed at the outcome level. <h3>Main Outcomes and Measures</h3> Tax pass-through rate for prices, percentage reduction in SSB demand, and price elasticity of demand for sales and consumption. Heterogeneity was assessed using τ<sup>2</sup>and the<i>I</i><sup>2</sup>statistic. <h3>Results</h3> A total of 86 articles were eligible, with 62 studies contributing to the meta-analysis. The overall tax pass-through rate was 82% (95% CI, 66% to 98%;<i>P</i> &lt; .001,<i>I</i><sup>2</sup> = 99%), suggesting tax undershifting. The demand for SSBs was highly sensitive to tax-induced price increases, with the price elasticity of demand of −1.59 (95% CI, −2.11 to −1.08;<i>P</i> &lt; .001;<i>I</i><sup>2</sup> = 100%) and a mean reduction in SSB sales of 15% (95% CI, −20% to −9%;<i>P</i> &lt; .001;<i>I</i><sup>2</sup> = 100%). There was no evidence of substitution to untaxed beverages, and changes in SSB consumption were not significant. The narrative synthesis found reformulation and reduced sugar content of taxed beverages for tiered taxes, cross-border shopping in most studies of local-level taxes, and no negative changes in employment. Data on the heterogeneity of SSB tax outcomes across subpopulations were limited. <h3>Conclusions and Relevance</h3> In this systematic review and meta-analysis of implemented SSB taxes worldwide, SSB taxes were associated with higher prices and lower sales of taxed beverages.
The role of real-world evidence (RWE) registries using NGS testing to address cancer health disparities (CHD) in small community oncology practices.
Authors: Asutosh S. Gor, Kashyap B. Patel, Viral Rabara, Natasha Clinton
Journal: Journal of Clinical Oncology (2022)

e18519 Background: CHD may result from multiple factors, including access to care, screening, and clinical trials; limited uptake of biomarker and next-generation sequencing (NGS) testing; and unfavorable social determinants of health. CHD may contribute to almost 34% of deaths among adult cancer patients and additional spending of $230 billion. Addressing CHD could result in an indirect savings of as much as $1 trillion over 3 years (AACR, CDR, 2020). Biomarker testing enables the option of targeted treatment, providing better outcomes and reduced toxicity. The NGS testing rate is very low in some regions and among minority populations, and underuse worsens disparities. Carolina Blood and Cancer Care Associates (CBCCA) has created best practices to improve biomarker testing and provide standard-of-care treatment in advanced cancer. Methods: As a part of a pledge to decrease CHD, CBCCA partnered with 2 national NGS testing vendors to create a RWE registry to identify appropriate patients and provide access to NGS biomarker tests for somatic mutations, including whole exome sequencing (WES). Liquid biopsy was made available when tissue was unavailable. Results: CBCCA has 1 suburban and 1 rural location, with an ethnically diverse population. Regular care was provided for 1466 of the 1786 unique cancer patients seen in 2021, and 442 participated in a RWE registry. Nonparticipants were survivors having routine follow-up care (n = 512), patients with early-stage or noninvasive disease (510), or patients who refused testing because they were responding to ongoing treatment or had reservations. NGS testing was obtained for 354 patients, 31% of whom were members of ethnic minority groups. Liquid biopsy was used for 133 samples, and the remaining 221 were analyzed with somatic NGS panels or WES. Of the liquid biopsies, 24 patients had actionable mutations; an additional 52 had findings of germline implications. Actionable mutations that could be treated with an FDA-approved drug were identified using tissue-based NGS testing in 38 pt. In tissue-based testing, WES detected more results with germline implications, compared to somatic testing alone. Another 64 tests found mutations treatable with an approved drug in another tumor type. The NGS and biomarker testing rate (either tissue or liquid biopsy) was 84% of eligible pt. Of the patients tested with NGS, clinically actionable variants that could be treated with an approved agent were found in 23% (same tumor type) and 28% (another tumor type). Another 40% of patients had results with germline implications, of which P53 deletion was the most common finding. Conclusions: It is feasible to increase the NGS testing rate in appropriate situations. In this study, actionable mutations impacting treatment selection were found in up to 25% of patients where targeted therapy could be offered.
FGF15/FGF19 is involved in the development of cardiac hypertrophy
Authors: A Planavila, S Moron-Ros, F Villarroya, A Gavalda-Navarro
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Funded by MCIN/AEI/ 10.13039/501100011033 and, by “ERDF A way of making Europe”, by the “European Union” Introduction FGF15 (and its human orthologue, FGF19) are members of the endocrine FGF family. They are produced by ileal enterocytes in response to bile acids. The liver is its main target tissue but recent studies indicate that FGF19 also regulates skeletal muscle mass and adipose tissue plasticity. Objective To determine the role of the enterokine FGF15/19 during the development of cardiac hypertrophy Methods Circulating FGF19 levels were assessed in patients with heart failure (HF) and myocardial infarction. The hypertrophic response was characterized in Fgf15-null mice subjected to a high-fat diet for 16 weeks or isoproterenol infusion with osmotic minipumps for 7 days. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral (Ad-Fgf15) and adeno-associated vectors (AAV8-Fgf19) for 1-week or 3-weeks injection, respectively. Results In humans, we found that the FGF19 levels were significantly reduced in patients suffering from heart failure or myocardial infarction, reciprocally to FGF21 levels. We found that mice lacking Fgf15 do not develop cardiac hypertrophy in response to high-fat diet or isoproterenol induced cardiac hypertrophy. Specifically, we found that the ratio heart weight/tibia length (HW/TL), the quantification of cardiomyocyte area and the hypertrophy marker gene atrial natriuretic factor (Anf) -as measures of cardiac hypertrophy development- were reduced in Fgf15-null mice subjected to hypertrophy compared to their corresponding wild-type mice. By contrast, we found that experimental increases in FGF15 or FGF19 induced cardiac hypertrophy development in vivo, characterized by an increase in the HW/TL ratio, area of the cardiomyocytes and hypertrophy marker genes. Conclusions We stablish a cross-talk between the intestine and the myocardium through the enterokine FGF15/19 which seems a key factor required for cardiac hypertrophy development.
Predictors of severe CRS in longitudinal CAR T-cell clinical trial data.
Authors: Caleb Strait, Jacob Aptekar, Michael W. Kattan, Vibhu Agarwal
Journal: Journal of Clinical Oncology (2022)

2540 Background: Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor (CAR) T-cell therapy and there is a limited understanding of its risk factors. Known markers of severe CRS lack specificity or require central lab facilities, making them unsuitable for safety surveillance during trials. Using data from anti-CD19 CAR-T trials from the Medidata Enterprise Data Store (MEDS) we analyzed laboratory tests with repeated measurements to identify differences in trends that persist across a variety of study designs, sponsors and indications. Our aim was to capture the dynamic response to lymphodepletion (LD) and CAR-T infusion events in the time course values of laboratory markers and compare these in the severe CRS (grade 3 and higher) and non severe CRS groups. Methods: Subjects in the anti-CD19 CAR-T trials obtained from MEDS had relapsed or refractory disease in one of the following: B Acute Lymphoblastic Leukemia (B-ALL), Mantle Cell Lymphoma (MCL), Non-Hodgkin Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL). Laboratory markers with repeated measurements across all studies were included in the analysis. Response to LD, CAR-T infusion and the onset of hematologic recovery was modeled with piecewise linear splines with knots at the boundaries of the pre LD (-18d to LD), the LD - infusion and post infusion (1d to 6d and 6d to 18d) intervals using linear mixed effects regression. Results: The dataset consisted of 542 patients: 24.1% B-ALL, 44.4% NHL, 16.8% MCL, 14.6% DLBCL; mean age 54.8 (SE = 0.021) years, 67.7% males. 27.3% had CRS 3+ with a median time-to-event of 4.5 days. Average rates of change (units per day) for the severe CRS subjects in the pre LD, LD-infusion and post infusion intervals relative to the rest are shown (table). None of the markers had a significant relative rate of change prior to LD. The average change in Albumin, Platelets and Hematocrit was consistently lower in severe CRS patients. Conclusions: Longitudinal laboratory marker data may be used to derive predictors of severe CRS in patients undergoing anti-CD19 CAR-T therapy. While some of the laboratory markers discussed above corroborate earlier findings, modeling the pre and post infusion kinetics can yield novel markers with improved precision in severe CRS prediction and better patient safety. [Table: see text]
Assessment of tumour infiltrating subpopulations and pathological complete response using multiplex immunohistochemistry and digital pathology in early HER2+ breast cancer.
Authors: Camille Hurley, Laetitia Lacroix, Katherine Sheehan, Mairi Lucas, Rachel Buckley, Anna Blümel, Sinead Toomey, Bryan T. Hennessy, John Crown, Catherine Sautes-Fridman, Darran O'Connor
Journal: Journal of Clinical Oncology (2022)

e15041 Background: The treatment of HER2+ breast cancer (BC) has improved substantially with the use of targeted therapies, and patients achieving pathological complete response (pCR) following neoadjuvant therapy have significantly improved disease free survival. However, there is currently no way to determine which patients are most likely to respond to neoadjuvant HER2-targeting treatment. Growing evidence indicates tumour infiltrating lymphocytes influence HER2+ BC outcome. We hypothesize that a deeper investigation of the immune landscape of HER2+ patient tumours may improve patient stratification and identify an immune profile associated with pCR. Methods: 3plex immunohistochemistry panels identifying immune cell subpopulations and tertiary lymphoid structures were applied to HER2+ BC tumors (pre-treatment N=19, post-treatment N=9) of patients of the neoadjuvant TCHL clinical trial (NCT01485926), who received HER2-targeting therapy. Quantitative analysis of CD3+, CD20+, DC-Lamp+, CD4+, and CD8+ immune cells on multi-labelled whole-slide images of TCHL tumor sections was performed using artificial intelligence image analysis models. Patient-specific densities of each cell type in tumor regions were determined to facilitate assessment of pre-treatment differences in target immune subpopulations in complete, partial, and non-responders. Results: Statistical analysis demonstrated a trend for higher densities of each immune subpopulation in pre-treatment biopsies of pCR vs. non-pCR patients. Patient categorisation based on median threshold demonstrated patients achieving pCR are more frequently high for each immune cell type assessed, while non-pCR patients are more frequently in the low category. Investigation of association of pre-treatment immune infiltrate with clinicopathological features demonstrated trends for higher levels of T-cell infiltration in later stage and hormone receptor negative patients. Conclusions: Multiplex IHC is an optimal technique for the concurrent assessment of multiple target markers in patient tissue, which can be quantitatively analyzed in a high throughput manner using AI models. The findings of this preliminary study support recent evidence regarding the role of tumor infiltrating immune cells in HER2+ BC outcome and warrant further investigation in a larger cohort.
Safer food, better health
Authors: None The Lancet Microbe
Journal: The Lancet Microbe (2022)

June 7 marks World Food Safety Day and the theme—"Safer food, better health"—is simple but relevant. As The Lancet Microbe goes to press, ten European countries and the USA have reported Kinder chocolate products contaminated with salmonella. As of April 25, the outbreak had caused more than 150 suspected cases of salmonellosis with several hospitalisations, mainly in children younger than 10 years. The health and economic consequences have been felt worldwide with Kinder products being recalled in at least 113 countries.
Updates to the Management of Patients With Relapsed or Refractory Indolent Follicular and Marginal Zone Lymphomas
Authors: Ann S. LaCasce, Ariela Noy
Journal: Journal of the National Comprehensive Cancer Network (2022)

Although follicular lymphoma (FL) and marginal zone lymphoma (MZL) share similarities, the 2 diseases have distinct biologic differences that affect their presentation and treatment. Stage I disease is more common in MZL than in FL due to marginal zone biology, for example, and stage I MZL is curable by surgery or radiation therapy. Newer therapies for both FL and MZL provide chemotherapy-free options, but they are not identical. Brüton’s tyrosine kinase inhibitors are active in relapsed or refractory MZL but not in FL, for example. CAR T-cell therapy has just been approved for treatment of FL and is an ongoing area of investigation for both diseases.